1. Field of the Invention
The present invention relates to novel substances KF-1040T4A, KF-1040T4B, KF-1040T5A and KF-1040T5B having an inhibitory activity for lipid metabolism, and a process for producing such substances.
2. Description of Related Art
There are known anti-obesity drugs and drugs for hyperlipemia. For example, a centrally acting anorectic, Majindol (A. J. Stunkard and J. Rush, Ann. Intern. Med., 81, 526-533, 1974) reduces the biosynthesis of lipids by suppressing appetite, which may, however, be harmful for health in some cases owing to the reduction of appetite. Therefore, it has been desired to develop a new anti-obesity drug or a therapeutic drug for hyperlipemia which has no such side effect.
On the other hand, it has recently became clear that the hydrolysis of sphingomyelin, which is one of lipids constituting mammalian plasmamembrane, is involved in the intracellular signal transduction by cytokine, such as interleukin 1xcex2 or tumor necrosis factor xe2x88x92xcex1 [Y A. Hannun, J. Biol. Chem., 269, 3125-3128 (1994) and R. Kolesnick and D. W. Golde, Cell, 77, 325-328 (1994)], in the intracellular signal transduction upon activation of T cells [L. M. Boucher et al., J. Exp. Med., 18, 2059-2068 (1995); A. Ochi, Medicinal Immunol., 28, 397-401 (1994)], in diseases such as arteriosclerosis, thrombosis, inflammations and so on, and in the immunoregulation mechanisms.
However, any prophylactic or therapeutic medicament for these diseases has not yet been developed in practice from a drug which specifically and strongly inhibits sphingomyelinase, a hydrolase of sphingomyelin.
In recent years, with the improvement of diet, there has been an increase of life-style related diseases, especially obesity and hyperlipemia caused by the accumulation of triacylglycerols. These diseases have caused serious problems in the therapeutic and preventive medical sciences as the cause or potentiation of various diseases. Diseases which tend to accompany obesity and hyperlipemia caused by the accumulation of triacylglycerols include arteriosclerosis, fatty liver, hypertension, diabetes, and so on. Currently, the population of the patients with these diseases is increasing.
Obesity refers to a physical state in which the stored fat, constituted mainly of triacylglycerols, is accumulated excessively in the body, and is ascribed to an increased synthesis of triacylglyceroles causing extraneous accumulation of fat in the adipocytes. Also, triacylglycerolaemia is believed to be triggered by facilitation of triacylglycerol synthesis in the intestines and the liver, which causes a lipoproteineamia with a high concentration of triacylglycerols in the blood.
Therefore, it is assumed that any substance exhibiting an inhibitory action on diacylglycerol acyltransferase which involves the selective synthesis of triacylglycerols may have the ability to suppress the accumulation of triacylglycerols and may be effective for these diseases.
Under the circumstances, it is worthwhile in the therapy of obesity and hyperlipemia and of various adult diseases such as arteriosclerosis and so on, originating therefrom, to provide a substance having an activity of inhibiting diacylglycerol acyltransferase.
Furthermore, it is also expected that a substance having an activity of inhibiting sphingomyelinase which causes hydrolysis of sphingomyelin, a plasmamembrane constituting lipid, may be useful as an antiarteriosclerotic agent, an antithrombotic agent, an anti-inflammatory agent, and an immunosuppressor, based on a novel function not found heretofore.
The inventors have conducted various studies for metabolic products produced by microorganisms and found that substances which have activities for inhibiting diacylglycerol acyltransferase and sphingomyelinase are produced in the culture medium during the cultivation of a fungal strain KF-1040 newly separated from a sea weed. These active substances capable of inhibiting the metabolism of lipids have been then isolated from the culture medium and purified, wherefrom substances having the chemical structures represented by the formulae [I], and [II] described below have been found. Since the substances having the chemical structures have not been known heretofore, the inventors have named them substances KF-1040T4A, KF-1040T4B, KF-1040T5A and KF-1040T5B.
The present invention has been accomplished based on such findings and it relates to the stereoisomers KF-1040T4A and KF-1040T4B comprising the compound represented by the following formula [I], 
and the stereoisomers KF-1040T5A and KF-1040T5B represented by the following formula [II], 
The present invention further relates to a process for producing novel substances KF-1040T4A, KF-1040T4B, KF-1040T5A and KF-1040T5B comprising the steps of culturing a microorganism which belongs to the genus Gliocladium and has the ability to produce substance KF-1040T4A and/or KF-1040T4B and/or KF-1040T5A and/or KF-1040T5B in a culture medium, causing to accumulate the substance KF-1040T4A and/or KF-1040T4B and/or KF-1040T5A and/or KF-1040T5B in the culture medium, and harvesting the substance KF-1040T4A and/or KF-1040T4B and/or KF-1040T5A and/or KF-1040T5B from the culture medium.
The present invention also relates to a process for producing the substances KF-1040T4A, KF-1040T4B, KF-1040T5A and KF-1040T5B, wherein a microorganism which belongs to the genus Gliocladium and has the ability to produce substance KF-1040T4A and/or KF-1040T4B and/or KF-1040T5A and/or KF-1040T5B is Gliocladium sp. KF-1040 (FERM BP-6251).
The present invention further relates to a microorganism which belongs to the genus Gliocladium and has the ability to produce substance KF-1040T4A and/or KF-1040T4B and/or KF-1040T5A and/or KF-1040T5B. The microorganism having the ability to producing the substances KF-1040T4A, KF-1040T4B, KF-1040T5A and KF-1040T5B represented by the formulae [I] and [II] (hereinafter referred to as xe2x80x9csubstance KF-1040 producing fungusxe2x80x9d) belongs to the genus Gliocladium and, for example, the fungal strain Gliocladium sp. KF-1040 isolated by the inventors is an example to be utilized most effectively in the present invention. The myocological properties of the present strain KF-1040 are as described below.